Acrylonitrile-based oxathiapiprolin analogues: A new structural strategy for oomycete fungicide development

Oomycete pathogens cause destructive crop diseases worldwide, leading to substantial economic losses and posing a continuous threat to agricultural sustainability. Oxathiapiprolin, the first piperidinyl-thiazole-isoxazoline fungicide, has revolutionized oomycete control by targeting oxysterol-binding proteins; however, its structural complexity and dependence on the isoxazoline moiety limit synthetic accessibility and further optimization. In this study, a series of oxathiapiprolin-inspired analogues was rationally designed by replacing the isoxazoline ring with an acrylonitrile fragment, a motif known for its conformational rigidity and tunable electronic properties. Compounds 5a - 5e , 11a-11i , and 15a - 15q were synthesized and evaluated for antifungal activity against oomycete pathogens. Among them, compound 15l exhibited outstanding in vivo efficacy, achieving 100% control of cucumber downy mildew at 1.25 mg L −1 . Structure-activity relationship analysis revealed that electron-withdrawing substituents, particularly the 2,6-difluoro substitution pattern, significantly enhanced biological activity. Molecular modeling indicated that compound 15l adopts a binding conformation generally similar to that of oxathiapiprolin but engages in distinct interactions, including hydrogen bonding with Gln31 and hydrophobic contacts with Lys114 and Met174. These results demonstrate that the acrylonitrile motif can serve as an effective bioisosteric replacement for the isoxazoline ring while retaining significant fungicidal activity. This work expands the structural diversity of oxathiapiprolin analogues and provides a promising, synthetically accessible scaffold for the development of next-generation oomycete fungicides.